Evidence from our recently conducted molecular epidemiology study of oral cancer suggests HPV is an independent risk factor in the development of these tumors. Human papillomavirus (HPV) infection is causally associated with greater than 95 percent of carcinomas of the cervix and is often found in other genital cancers as well as in laryngeal cancers. Because of the link between HPV and these tumors, early identification of the virus may provide a crucial marker of high-risk susceptibility and for early detection. In our recent study of oral cancer, cancer cases were significantly more likely to be detected with HPV in cytology specimens from the oral cavity compared with those of matched healthy controls: 30 percent v. 18 percent. Over 24 percent of the cancer cases compared with only 11 percent of the controls were infected with oncogenic mucosal HPV types whereas there was no difference between cases and controls in the frequency of detecting nononcogenic-mucosal (1 percent in cases or controls) or nonmucosal types (4 percent each group). Based on the results of our current study, we propose here to focus on the association between oral cancer and potential molecular and genetic mechanisms that are involved in HPV-induced carcinogenesis: viral gene presence and expression, viral load, susceptibility to viral infection and/or carcinogenesis due to p53 polymorphism, and alterations in viral gene expression by mutagenesis and/or integration. The aims of this study are to: 1) determine whether oral carcinomas harbor and express DNA genomes of oncogenic mucosal HPV types and whether HPV types/variants found in oral cancer biopsies match those in oral cytology specimens as potential markers in clinical screening; 2) characterize the potential influence of polymorphism in the tumor suppressor gene p53 on the susceptibility to HPV infection and/or oral carcinogenesis; and 3) evaluate the potential role of altered HPV gene expression due to mutations in the viral control region or due to viral DNA integration in the cellular genome in oral cancer development and progression. This study (a collaboration between clinicians, molecular epidemiologists and pathologists who are members of the U. Iowa Cancer Center) will elucidate the molecular and genetic mechanisms involved in HPV-associated carcinogenesis in the oral cavity and identify potential markers of early diagnosis and/or prognostic indicators of oral cancer.